People @ Bishop Lab - Mouse Genome Project at BCM

CURRENT PROJECT:

The overall focus of my laboratory concerns the genetics of germ cell development and fertility. Two main themes are being developed: (i) The role played by mouse Y chromosome genes in male development and spermatogenesis and (ii) The use of novel mouse mutants to examine the genetics of specific stages of germ cell development. All aspects of the mammalian male phenotype, including spermatogenesis, are due either directly or indirectly to the activity of the Y chromosome. The expression of the Y encoded transcription regulator, Sry, initiates primary sex determination by inducing the indifferent embryonic gonad to form a testis. This testicular environment, in turn initiates secondary sexual differentiation and causes the early germ cells to follow the male pathway by forming amitotic prospermatogonia, rather than meiotic oocytes. Our laboratory is working on identifying and characterizing Y-located genes involved in spermatogenesis. We have focused on a ~1Mb deletion (Sxrb) in the minute Y short arm, which appears to carry most of the genetic information needed to complete spermatogenesis. In collaboration with the Baylor Genome Center, we are sequencing and annotating ~1.5 Mb spanning this deletion. Our working hypothesis is that the specific Y genes identified will be needed at specific stages of spermatogenesis and spermiogenesis. We have recently developed an improved technology for efficiently targeting Y chromosome genes in ES cells, and are using it to directly test this hypothesis. Using positional cloning techniques, we are examining the earliest stages of primordial germ cell (PGC) migration and proliferation using the germ cell deficient mutant, gcd. In homozygotes of this strain, only about 25 percent the normal number of PGC's are seen in the embryonic gonadal ridge at 11.5 dpc. This results in sterility due to severe oligospermia in adult males and premature ovarian failure in adult females. Embryonic testis formation, necessary for the PGC's to develop along the spermatogenic pathway, is being analyzed through the use of a new mouse mutant Odd Sex, (Odsex). In this mutant, XXOds mice develop as males despite the complete absence of the Y chromosome and the Sry gene. We have put forward the hypothesis that specific elements which regulate gonad specific Sox9 expression are deleted leading to XX sex reversal. We are using the juvenile spermatogonial depletion mutant (jsd) to examine spermatogonial stem cell renewal and differentiation. Our working hypothesis is that the jsd phenotype is caused by an error in a novel, early germ cell signal transduction pathway, mediated by the JSD protein. These models closely mimic aspects of human infertility and sex-reversal conditions seen in Sertoli Cell Only syndrome, Premature Ovarian Failure and XX(Y-) sex reversal. As such, they represent attractive animal models for investigating the regulation of these developmental processes and provide an important component in the generation of knowledge-based therapies.